A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.

Autor: Dalton HM; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Young NJ; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Berman AR; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Evans HD; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Peterson SJ; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Patterson KA; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Chow CY; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2024 Oct 28; Vol. 20 (10), pp. e1011458. Date of Electronic Publication: 2024 Oct 28 (Print Publication: 2024).
DOI: 10.1371/journal.pgen.1011458
Abstrakt: DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Dalton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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